U.S. Pat. No. 3,127,413 (Gray) discloses octahydroisoindoles of the formula: ##STR1## wherein: Ar represents a radical from an aromatic ring system which is monocyclic or bicyclic;
Alk represents on alkylene chain, straight or branched, containing at least one and not more than three carbon atoms; PA1 R is H or acyl; and PA1 R' is lower-alkyl. PA1 R.sup.2 is NR.sup.4 R.sup.5 Br, OH, phenyl, or CN; PA1 R.sup.3 is H or OH; and PA1 R.sup.4, R.sup.5 are H or lower alkyl. PA1 R.sup.2 is C.sub.1 -C.sub.8 alkyl, C.sub.2 -C.sub.8 alkenyl, cyclohexyl-C.sub.1 -C.sub.4 alkyl, 9-fluorenyl, 1-Cyano-1-phenylmethyl or phenyl-C.sub.1 -C.sub.4 alkyl. PA1 m is 1 or 2; PA1 n is 1 or 2; PA1 p is 1 or 2; PA1 q is 1 or 2; PA1 R.sup.a =H, alkyl of 1 to 6 carbons, halogen, PA1 alkoxy of 1 to 6 carbons or OH, and ##STR12## where: s=1 or 2, PA1 B=S, CH.sub.2 or CH.dbd.CH, PA1 A=(CH.sub.2).sub.2, (CH.sub.2).sub.3 or CH.dbd.CH, PA1 R.sup.b =H or alkyl of 1 to 6 carbons; PA1 a) Cis-2-(4'-fluorophenethyl)-6-(4"-fluorophenyl)-6-hydroxydecahydroisoquinol ine. PA1 b) Cis-2-(4'-pyridylmethyl)-6-(4"-fluorophenyl)-6-hydroxy decahydroisoquinoline. PA1 c) Cis-2-(4'-pyridylmethyl)-6-(4"-fluorophenyl)-6-hydroxydecahydroisoquinolin e, dihydrochloride salt. PA1 d) Trans-2-Benzyl-6-(4'fluorophenyl)-6-hydroxy decahydroisoquinoline. PA1 e) Trans-2-Benzyl-6-(4'-fluorophenyl)-6-hydroxy decahydroisoquinoline, major hydroxy epimer. PA1 f) Trans-2-Benzyl-4-(4'-Fluorobenzyloxy)-decahydroisoquinoline. PA1 g) Trans-2-Benzyl-4-(4'-fluorophenoxy)-decahydroisoquinoline.
The octahydroisoindoles are useful as tranquilizing agents and for potentiating the action of barbiturates.
Processes for preparing trisubstituted perhydro isoindolines of the following formula are described by Achini et al, Helvetica Chimica Acta, 57, Fasc. 3, pp. 572-585 (1974): ##STR2## wherein: R.sup.1 is H or COC.sub.6 H.sub.5 ;
German Patent 3721723 (Hoechst AG) describes substituted 6-Oxo-Decahydroisoquinolines of the formula: ##STR3## wherein: R.sup.1 is benzyl, C.sub.1 -C.sub.4 alkoxycarbonyl or 2,2,2-Trichloro-ethoxycarbonyl; and
These compounds are useful as tranquilizing agents.
U.S. Pat. No. 3,689,492 (Schroeder et al.) discloses a compound having the formula: ##STR4## This compound is useful as an analgesic in warm-blooded animals.
U. K. Patent No. 1,141,664 (Jansen) discloses piperidine compounds having the formula: ##STR5## wherein Y is Ar or Ar.sup.3 and Z is Ar.sup.1 or Ar.sup.2, Ar being phenyl, halophenyl or lower alkoxy phenyl, Ar.sup.1 being dihalophenyl, trihalophenyl, lower alkyl - halo- phenyl or trifluoromethy - halo - phenyl, Ar.sup.2 being halophenyl and Ar.sup.3 being di - halo - phenyl or lower alkyl - halo - phenyl, with the proviso that when Y is Ar then Z is Ar.sup.1, and when Y is Ar.sup.2 then Z is Ar.sup.2.
These compounds are useful as psychotropic and neuroleptic agents.
European Patent Application No. 0 196 132 (Kennis and Vandenberk) discloses compounds having the formula: ##STR6## wherein X is O or S and Q is a radical of formula ##STR7## or a radical of formula ##STR8## These compounds are useful as antipsychotics.
Janssen et al., Journal of Med. and Pharm. Chem., vol. 1, 281-297 (1959), disclose compounds having the formula: ##STR9## wherein L=H or F and R=H, F, Cl, or CH.sub.3). The authors discuss the CNS depressant properties of these compounds.
Compounds of the present invention demonstrate sigma receptor affinity. It is this sigma receptor affinity of the compounds of the present invention which makes them so advantageous over the compounds in the prior art. Traditionally, antipsychotic agents have been potent dopamine receptor antagonists. For example, phenothiazines such as chlorpromazine and most butyrophenones such as haloperidol are potent dopamine receptor antagonists. These dopamine receptor antagonists are associated with a high incidence of side effects, particularly Parkinson-like motor effects or extra-pyramidal side-effects (EPS), and dyskinesias including tardive dyskinesias at high doses. Many of these side effects are not reversible even after the dopamine receptor antagonist agent is discontinued.
The present invention is related to antipsychotic agents which are sigma receptor antagonists, not traditional dopamine receptor blockers known in the art, and therefore the compounds of the present invention have low potential for the typical movement disorder side-effects associated with the traditional dopamine antagonist antipsychotic agents while they maintain the ability to antagonize aggressive behavior and antagonize hallucinogenic-induced behavior.